Heart failure (HF) is a widespread and debilitating cardiovascular disease that affects nearly 23 million people worldwide with approximately 2 million new patients diagnosed annually. A distinctive hallmark of heart failure is autonomic imbalance, consisting of increased sympathetic activity and decreased parasympathetic tone. Restoration of parasympathetic activity to the heart has recently emerged as a promising new therapeutic approach to inhibit the progression of heart failure and risk of sudden cardiac death. Our preliminary results provide critical new information for the field that identifies a novel target that could restore parasympathetic cardiac activity in an animal model of left ventricular hypertrophy that progresses to heart failure. The overarching hypothesis of the current proposal is that hypothalamic paraventricular nucleus of the hypothalamus (PVN) oxytocin neurons are essential for activating parasympathetic cardiac vagal neurons (CVNs) in the brainstem. In animals with trans-aortic compression (TAC), which leads to left ventricular hypertrophy that progresses to heart failure, the release of oxytocin, and activation of CVNs, is diminished. Perhaps more importantly, our preliminary results indicate selective restoration of oxytocin activity restores the synaptic release of oxytocin from PVN neurons, the excitatory neurotransmission from PVN to parasympathetic CVNs, improves cardiac function and favorably alters the indices of cardiac ischemia and damage that occurs in untreated animals. In this proposal we will build upon our preliminary results to address three Specific Aims: 1) Determine if there is reduced release of oxytocin from paraventricular neurons of the hypothalamus fibers in the brainstem and blunted excitation of cardiac vagal neurons in heart failure diseased animals. Furthermore test if selective chronic activation of oxytocin neurons in the PVN acts to restore both the release of oxytocin in the brainstem and activation of parasympathetic cardiac vagal neurons. 2) Test the hypothesis that chronic activation of PVN oxytocin neurons mitigates the progression of cardiac dysfunction that occurs in untreated HF disease animals. Left ventricular (LV) developed pressure, contractility, and electrical synchronization will be measured to assess mechanisms of improved cardiac function. 3) Examine if indices of cardiac ischemia, including in-vivo electrocardiograph (EKG) abnormalities, increased fluorescence of epicardial NADH (fNADH), and the formation of fibrotic (scar) tissue are absent or blunted in animals with chronic activation of hypothalamic PVN oxytocin neurons compared to untreated HF animals. The studies in this proposal will either support, or refute our hypothesis that PVN oxytocin neuron activation can restore diminished parasympathetic cardiac tone and blunt the deleterious progression of cardiac function alterations that occur in animals with LV hypertrophy, cardiac dysfunction and heart failure. This will provide an important foundation for future clinical studies, giving this work high translational potential and significance.